This invention relates to new pharmaceutical compositions that are useful in topical application for the treatment of fungal nail infections, in particular onychomycosis.
Fungal infections of the nail are much more prevalent than is commonly perceived. It is often understood to be a niche problem, affecting only a few people. In fact, it is the most common disease of the nail, affecting about 100 million patients in Europe and North America. Prevalence is about 10% in the general population and over 25% in the over-50s.
Onychomycosis is the most common fungal disease of the nail and affects about 6 to 8% of the adult population. Onychomycosis can affect both toenails and fingernails and is chiefly manifest by thickening and discoloration of the nails. This results in the formation of opaque, thick and/or friable nail lesions caused by the invasion of fungi. The nail becomes dry, and breaks or flakes, often exhibiting a yellowish colour.
Nails that become hard and thick, make the care of the nail more difficult. Infected toenails can grow so thick that shoes became uncomfortable to wear. In extreme cases, destruction of the nail may result. Additionally, a perceived unsightliness in infected nails can lead to confidence and/or self esteem problems in situations when the hands and/or feet are necessarily exposed.
In addition to onychomycosis, about 40% of all patients with psoriasis are affected by changes in the nail. Dryness and/or superficial damage can also result in unsightly and discolored nails.
Nail fungus is also a very difficult condition to treat. Treatment times are often long; it can take a year or more for an infected nail to come away and a healthy new nail to grow out. Such longevity of treatment is known to cause poor compliance, meaning that the majority of patients are poorly treated or, in essence, untreated.
Significant effort has been directed towards research into alternative and/or better treatments of fungal infections of keratinous structures such as the nail.
Much of the research effort has been directed towards pharmaceutical formulations that attempt to administer a recognized antifungal compound, such as imidazoles, triazoles, thiazoles, echinocandins and allylamines (hereafter “antifungal drug compounds”) into the nail structure. However, the problem of obtaining distribution of sufficient concentrations of such antifungal drug compounds throughout the nail and into the nail bed has proven to be a difficult one to solve. Thus far, a completely satisfactory solution eludes practitioners. Promising laboratory results for new formulations comprising antifungal drug compounds have often been followed by disappointing result in the clinic.
An efficacious pharmaceutical formulation that does not comprise an antifungal drug compound as such (including any of those listed above or hereinafter) is disclosed in international patent application WO 87/04617, U.S. Pat. No. 5,525,635 and European Patent No. EP 292 495 B1. Here, a composition for the treatment of inter alia mycosis of the skin and nails is disclosed that comprises, as its main active components, propylene glycol and urea, although lactic acid may also be included.
The efficacy and safety of this formulation have been documented in several clinical trials (see, for example, Emtestam, Kaaman and Rensfeldt (2012), Mycoses, 55, 532 (2012) and Faergemann, Gullstrand and Rensfeldt, Journal of Cosmetics, Dermatological Sciences and Applications, 1, (2011)). Furthermore, a product based on this formulation is sold under the trademark Emtrix®, or Nalox®. It is indicated primarily in the treatment of nail discoloration and damage caused by fungal nail infection or psoriasis.
Emtrix® ingredients are all GRAS (General Regarded as Safe by FDA) listed compounds and are fully biodegradable. The product is free from preservatives and fragrances. It is applied as a solution directly to the damaged nail.
Despite the efficacy of this product, we have found that the chemical stability of the solution could be improved at higher storage temperatures. In particular, the urea in such formulations chemically degrades. This instability is unexpectedly solved by the addition of a triol, such as glycerol, to the liquid formulation.
Glycerol is commonly used as a constituent in cosmetic and pharmaceutical formulations. See, for example, international patent application WO 03/090736 and U.S. Pat. No. 8,158,138.
The use of urea hydrogen peroxide (or carbamide peroxide) as a whitening agent is known from U.S. Pat. No. 6,573,301 and U.S. Patent Application No. 2007/0098654. In Japanese patent application No. 2001-019610, a composition for skin (topical) application comprising urea is stabilised by the addition of a nucleotide in combination with an ester derived from a short fatty acid and glycerol.
International patent application WO 2012/110430 describes pharmaceutical compositions comprising solvents, in which urea is rendered in the solid state prior to application of the composition to e.g. the nail of a subject and evaporation of an organic solvent. Glycerol is mentioned as an agent that may be included to improve the “washability” of the composition after the organic solvent has evaporated.